This proposal presents a research career development program focused on the study of alcohol?s dose-dependent effects in neuroinflammation in a mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). I am currently an assistant professor of neurology at Dell Medical School at UT Austin. The outlined proposal builds on my previous research in neurobiology of sex differences, clinical training in neuroimmunology and integrates new domains of expertise in bioinformatics, alcohol and microbiome research, and basic science neuroimmunology. I will be guided by outstanding mentors and advisors, including Drs. Adron Harris (alcohol research), Hans Hofmann (bioinformatics), Sergio Baranzini (microbiome), Olaf Stuve (neuroimmunology), and William Schwartz (career guidance). The proposed experiments, didactics, and mentorship will enable me to transition to an R01 funded physician scientist in the cross disciplinary field of neuroimmunology and alcohol research. MS is a chronic autoimmune demyelinating disease of the central nervous system (CNS) and the leading acquired cause of neurological disability in young adults. The cause of MS is unknown. Although genes contribute to the disease risk, it is thought that environmental factors, such as diet and the gut microbiome contribute to a larger degree of the risk. Alcohol is a common dietary factor used by MS patients. Yet, despite its widespread use, potential for abuse and known gut, CNS and immune effects, alcohol?s role in MS is not well understood. The foundation of this proposal is based on my preliminary studies, in press in PNAS, demonstrating that moderate alcohol consumption leads to EAE amelioration, decrease in microglia in the spinal cord, and a shift of gut microbiota toward a regulatory phenotype in a sex-specific pattern, that collectively suggest a protective role of moderate alcohol in EAE and potentially in MS. Given known pro-inflammatory effects of alcohol, these studies raise the question of alcohol?s possible differential effects on neuroinflammation at high vs moderate doses. This proposal begins to address this question by evaluating alcohol?s dose-dependent effects on the peripheral and CNS immune system and the gut microbiome. Specifically, the aims of this proposal are (1) What are the peripheral and CNS immune cell subsets driving dose-dependent alcohol effects in EAE? Can adoptive transfer from alcohol-consuming mice recapitulate clinical symptoms in naive mice? and (2) Which gut microbiome constituents are responsible for alcohol?s dose-dependent effects in EAE? Can microbiome transfer from alcohol-consuming mice recapitulate clinical symptoms in naive mice? The scientific objective of this proposal is to begin to define alcohol?s dose-dependent effects in neuroinflammation by examining the immune system and the gut microbiome with the vision of generating hypotheses that can inform the direction and design of future diet studies in EAE and MS and expand the repertoire of available and targeted probiotics for MS patients.